Ethical Approaches to Genotype-Driven Research Recruitment This application addresses broad Challenge Area (02) Bioethics and specific Challenge Topic, 02-RR-101* "Recontact Issues in Genotype and Genome-Wide Association Studies." Many genotype and genome-wide association studies (GWAS) are conducted using a phenotype-driven approach: cases and controls are identified based on the presence or absence of a particular condition and analyses are undertaken to identify gene variants associated with that condition. The inverse-a genotype- driven approach-is receiving increasing attention as another powerful tool for understanding the impact of genetic variation. Cases and controls are defined among existing study populations based on the presence or absence of a particular genotype, and in-depth phenotyping is then conducted to understand the relationship between observable traits and the gene variant of interest. Enabling such a "bottom-up" approach to identifying and recruiting participants for follow-up studies could significantly advance the pace of genomic research by expanding the existing mechanisms for studying the functional significance of human genetic variation. Such approaches, however, present ethical challenges that have not been fully addressed. Genotype-driven recruitment is inextricably linked to the complex and much-debated issue of disclosing individual research results: when individuals are recontacted, what if anything should they be told about the genotype that led to their being recontacted? There is a fundamental tension between avoiding the introduction of potentially unwanted and uncertain information, and avoiding deception when explaining to prospective participants the purposes of the research and why they are being approached for participation. The purpose of this project is to develop evidence-based guidelines for addressing the ethical issues that arise in genotype-driven recontact and research recruitment. Specifically, this project involves 3 Clinical and Translational Science Award (CTSA) sites that will collaborate to: Explore the perceptions of research participants who have experienced genotype-driven recontact for further research participation. Investigate IRB chairs'experiences, opinions, and concerns about genotype-driven recontact and research recruitment. Formulate guidelines to assist IRBs and researchers in identifying balanced approaches to genotype-driven recontact and research recruitment. This proposal addresses 2 significant challenges: (a) the collection of empirical data on the novel concerns posed by genotype-driven recontact and recruitment;(b) the translation of such data into guidelines to assist researchers and IRBs. The results of our projects will be disseminated widely through a variety of mechanisms, including the CTSA Consortium. To sustain further progress on these complex issues, our proposal includes a plan to build a robust program of future research utilizing existing research networks to assess our guidelines with respect to stakeholder reactions, as well as implementation and outcomes. PUBLIC HEALTH RELEVANCE Genotype-driven approaches to identifying and recruiting participants in existing studies for follow-up research could significantly advance the pace of genomic discovery, thus helping to achieve the ultimate goal of enriched understanding of the role of genetic factors in common, complex diseases and improved pathways to risk reduction, diagnosis, and treatment. Recontacting research participants about additional studies based on genotype, however, involves ethical concerns that arise throughout the research process: during recruitment and consent for the original study, during the recontact process itself, and during recruitment and consent for the follow-up study. We propose to address these challenges through the collection of empirical data from multiple stakeholders about genotype-driven recontact and recruitment, and the development of evidence- based guidelines that provide appropriate protections for research participants, yet avoid overly restrictive policies that have a chilling effect on research and limit opportunities for those who would like to participate.